The use of traditional mechanism-based design strategies to design strategies to design antiviral agents targeting viral enzymatic activities has been hampered by problems with toxicity of the agents resulting from the tendency of viruses to "borrow" catalytic activities from the host. The goal of this proposal is to develop alternative methodologies that facilitate the use of high resolution structures of viruses and viral proteins to design alternative methodologies that facilitate the use of high-resolution structures of viruses and viral proteins to design antiviral agents that target virus-specific macromolecular interactions. The methodologies proposed are a hybrid between standard structure-based design methods and combinatorial chemistry. In this hybrid approach the target structure is used to derived a template for structurally biased-combinatorial libraries of compounds, and these libraries are screened for specific compounds with the desired antiviral activity. The method by-passes limitations inherent to standard structure-based design methods arising from lack of precision in macromolecular structure determinations, the inability to account for flexibility of the macromolecular target, and the inability of current computational methods to predict realistic free- energies of binding for a broad range of ligands and targets. By incorporating structural information into the library design the method focuses the diversity of the library on areas that are more likely to be productive, eliminating some of the problems (and occasional artifacts) generated by the very large diversity of the conventional unbiased combinatorial approaches. The methods will be used to address three specific goals: 1) The design of agents that bind the capsid of poliovirus and related entero- and rhinoviruses and inhibit conformational changes associated with cell entry. 2) The design of agents that interfere with an interaction between the herpes simplex virus DNA polymerase and its accessory protein UL42 which is required for processive DNA replication and infectivity. 3) The design of agents that bind to monomers or dimers of the major protein of hepatitis D virus and prevent the formation of functional oligomers.